New developments in diagnosis and non-surgical treatment of chronic pancreatitis

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1 bs_bs_banner doi: /jgh NUTRITIONAL FACTORS IN PANCREATOBILIARY DISORDERS New developments in diagnosis and non-surgical treatment of chronic pancreatitis Kazuo Inui, Junji Yoshino, Hironao Miyoshi, Satoshi Yamamoto and Takashi Kobayashi Department of Gastroenterology, Second Teaching Hospital, Fujita Health University School of Medicine, Nakagawa-ku, Nagoya, Japan Key words early chronic pancreatitis, extracorporeal shock-wave lithotripsy, pancreatic ductal stricture, pancreatic exocrine function, pancreatolithiasis. Accepted for publication 4 March Correspondence Prof. Kazuo Inui, Department of Gastroenterology, Second Teaching Hospital, Fujita Health University School of Medicine, , Otobashi, Nakagawa-ku, Nagoya , Japan. kinui@fujita-hu.ac.jp Disclosure of conflict of interest: No author has any financial or other conflicting relationships to disclose. Abstract Chronic pancreatitis is progressive and irreversible, leading to digestive and absorptive disorders by destruction of the exocrine pancreas and to diabetes mellitus by destruction of the endocrine pancreas. When complications such as pancreatolithiasis and pseudocyst occur, elevated pancreatic ductal pressure exacerbates pain and induces other complications, worsening the patient s general condition. Combined treatment with extracorporeal shock-wave lithotripsy and endoscopic lithotripsy is a useful, minimally invasive, firstline treatment approach that can preserve pancreatic exocrine function. Pancreatic duct stenosis elevates intraductal pressure and favor both pancreatolithiasis and pseudocyst formation, making effective treatment vitally important. Endoscopic treatment of benign pancreatic duct stenosis stenting frequently decreases pain in chronic pancreatitis. Importantly, stenosis of the main pancreatic duct increases risk of stone recurrence after treatment of pancreatolithiasis. Recently, good results were reported in treating pancreatic duct stricture with a fully covered self-expandable metallic stent, which shows promise for preventing stone recurrence after lithotripsy in patients with pancreatic stricture. Chronic pancreatitis has many complications including pancreatic carcinoma, pancreatic atrophy, and loss of exocrine and endocrine function, as well as frequent recurrence of stones after treatment of pancreatolithiasis. As early treatment of chronic pancreatitis is essential, the new concept of early chronic pancreatitis, including characteristics findings in endoscopic ultrasonograms, is presented. Introduction Chronic pancreatitis is a disease that causes chronic changes such as inflammatory cell infiltration, granulation tissue formation, irregular fibrosis, and loss of pancreatic parenchyma, with compromise of exocrine and endocrine functions. Progressive and irreversible, chronic pancreatitis is characterized by repeated episodes of acute inflammation over a long period, leading to digestive and absorptive disorders by destruction of the exocrine pancreas and to diabetes mellitus by destruction of the endocrine pancreas. Attention has been called to early chronic pancreatitis to encourage diagnosis and treatment before effective therapy becomes difficult. We discuss our experience with treatment of pancreatolithiasis and ductal stenosis. We also describe the new concept of early chronic pancreatitis. Pathology of chronic pancreatitis and complications. About patients in Japan have chronic pancreatitis, including some (75%) with pancreatolithiasis. 1 The maleto-female ratio among patients with chronic pancreatitis is 4.4:1. The most common etiology is alcoholism (77.8%) in men and idiopathic (47.6%) in women. The mean life expectancy of patients with chronic pancreatitis is about 10 years shorter than that of healthy people. The main cause of death is malignant tumors or complications such as renal failure related to diabetes mellitus. The course of chronic pancreatitis includes two phases: a compensated phase where symptoms such as abdominal pain, back pain, and anorexia occur repeatedly; and a decompensated phase characterized by digestive and absorptive disorders such as steatorrhea and diarrhea (exocrine insufficiency), and secondary diabetes mellitus (endocrine insufficiency). When complications such as pancreatolithiasis and pseudocyst occur, elevated pancreatic ductal pressure exacerbates pain and induces other complications, resulting in a worse clinical condition; treatment of these complications therefore is essential. Treatment of chronic pancreatitis Pancreatolithiasis. Treatment of pancreatolithiasis includes procedures such as pancreatic sphincteroplasty, 2 pancreaticojejunostomy, 3,4 and often more extensive operation such as pancreatic resection 5 and duodenum-preserving pancreatic head resection. 6 As for endoscopic treatment, Inui et al. 7 reported endoscopic 108 Journal of Gastroenterology and Hepatology 2013; 28 (Suppl. 4):

K Inui et al. Chronic pancreatitis: new developments pancreatic sphincterotomy in 1983, while Fujii et al. 8 reported pancreatic duct stenting in 1985.

11 reported that almost half of patients treated with endoscopy eventually underwent surgery.

9 Although surgical and endoscopic treatments remain the conventional therapies for pancreatolithiasis, usefulness of extracorporeal shock-wave lithotripsy (ESWL) has been recognized in Japan 12,13

Seven et al. 16 reported unsatisfying long-term outcomes following ESWL. In Europe, ESWL is employed either primarily or secondarily after failure of endoscopic pancreatolithotripsy.

2 K Inui et al. Chronic pancreatitis: new developments pancreatic sphincterotomy in 1983, while Fujii et al. 8 reported pancreatic duct stenting in Long-term outcome of surgery is recognized to be superior to that of endoscopic treatment in patients with painful obstructive chronic pancreatitis. 9,10 Cahen et al. 11 reported that almost half of patients treated with endoscopy eventually underwent surgery. However, endoscopic treatment (Figs 1 4) can be offered as a relatively non-invasive first-line treatment, with subsequent recourse to surgery in cases of failure and/or recurrence. 9 Although surgical and endoscopic treatments remain the conventional therapies for pancreatolithiasis, usefulness of extracorporeal shock-wave lithotripsy (ESWL) has been recognized in Japan 12,13 since Sauerbruch 14 reported this treatment in In the US, guidelines for treatment of chronic pancreatitis recommend endoscopic pancreatolithotripsy as first-line therapy, 15 as opposed to ESWL. Seven et al. 16 reported unsatisfying long-term outcomes following ESWL. In Europe, ESWL is employed either primarily or secondarily after failure of endoscopic pancreatolithotripsy. 17,18 Recently, Delhaye 19 reported that ESWL can be used as a first-line treatment when obstructive ductal stones cause Figure 1 Endoscopic retrograde cholangiopancreatography displays a filling defect (arrow) in the main pancreatic duct. Figure 3 A basket catheter is inserted into the main pancreatic duct to remove a pancreatic stone. Figure 2 Endoscopic pancreatic sphincterotomy. A papillotome is inserted into the orifice of the pancreatic duct. Figure 4 A pancreatic stone (arrow) is removed with a basket catheter. Journal of Gastroenterology and Hepatology 2013; 28 (Suppl. 4):

Chronic pancreatitis: new developments K Inui et al. dilation of the main pancreatic duct (MPD) upstream.

In our multicenter retrospective study, 13 results of combined treatment with ESWL and endoscopic lithotripsy in 555 patients with pancreatolithiasis were very good; the rate of lithotripsy

Stones recurred in 122 patients (22.0%). Of 504 patients with long-term follow-up, 24 (4.1%) required surgery.

3 Chronic pancreatitis: new developments K Inui et al. dilation of the main pancreatic duct (MPD) upstream. In Japan, ESWL is predominant with endoscopic treatment used adjunctively; 12,13,20,21 fragments of pancreatic stones pulverized by ESWL are collected using basket catheters. In our multicenter retrospective study, 13 results of combined treatment with ESWL and endoscopic lithotripsy in 555 patients with pancreatolithiasis were very good; the rate of lithotripsy effectiveness was 92.4%, stone disappearance, 72.6%, and alleviation of symptoms 91.1%. Complications developed in 35 patients (6.3%), including 30 (5.4%) who experienced acute pancreatitis. Stones recurred in 122 patients (22.0%). Of 504 patients with long-term follow-up, 24 (4.1%) required surgery. Lithotripsy with ESWL and endoscopic treatment preserve pancreatic exocrine function is the place with argument. Adamek et al. 22 reported that endoscopic management and ESWL does not prevent or postpone the development of glandular insufficiency. Yamamoto et al. 23 reported that exocrine pancreatic function (N-benzoil-L-tyrosil-para-amino benzoic acid test) was relatively preserved over the long term after treatment of pancreatolithiasis with ESWL. Pancreatic duct stenosis. Pancreatic duct stenosis in chronic pancreatitis elevates intraductal pressure and also is considered an etiological factor for both pancreatolithiasis and pseudocyst formation, making effective treatment vitally important. The main endoscopic treatment of benign pancreatic ductal stenosis is pancreatic duct stenting. Symptomatic improvement in terms of pain from chronic pancreatitis following this treatment is reported to occur in 74 94% of patients Stenting also is reported to be effective in facilitating removal of stones by ESWL. On the other hand, stenosis of the MPD is considered a risk factor for stone recurrence after treatment of pancreatolithiasis. In our experience, the recurrence rate in patients without stenosis was 13% as opposed to 50% in patients with stenosis. Stenting of a stenotic MPD has been performed with the aim of preventing recurrence of pancreatolithiasis; 27 however, we found no significant difference in stone recurrence rate between our patients with and without stenting. We therefore examined temporary insertion of a metallic stent to relieve stenosis, obtaining good results. 28 A delivery system is inserted through the stricture along a guide wire, leaving a fully covered expandable metallic stent, 8 mm in diameter and 40 mm in length, in place. The stent is not fully dilated immediately after insertion but is dilated 2 or 3 days after insertion (Fig. 5a,b). When the stent is withdrawn 7 days after insertion, the pancreatic stricture is dilated (Fig. 5c). Short-term metallic stenting is useful method for dilating strictures of the pancreatic duct and shows promise for preventing pancreatic stone recurrence after lithotripsy in patients with pancreatic stricture. We performed the procedure in five patients with advanced chronic pancreatitis, all of whom experiencing successful dilation without recurrence of pancreatic stones during a mean observation period of 45.6 months. We therefore believe that this short-term treatment will prove effective in preventing recurrence of pancreatolithiasis. Recently, Moon et al. 29 reported good results using a self-expandable metallic stent for pancreatic stricture. When those authors inserted a fully covered metallic stent or performed temporary stenting for 3 months, pancreatic strictures resolved in patients with advanced chronic pancreatitis. Such methods are promising in prevention of stone recurrence after lithotripsy in patients with pancreatic stricture. (a) (b) (c) Figure 5 (a) Endoscopic retrograde cholangiopancreatography displays a severe stricture (arrow) at the head of the pancreas and lots of filling defects in the main pancreatic duct. (b) A fully covered metal stent, 8 mm in diameter and 40 mm in length, is left in place. Pancreatic stones (arrow heads) are in the branch duct. (c) When the stent is withdrawn 7 days after insertion, the pancreatic stricture is dilated (arrow). 110 Journal of Gastroenterology and Hepatology 2013; 28 (Suppl. 4):

K Inui et al. Chronic pancreatitis: new developments PV Figure 6 Endoscopic ultrasonography shows hyperechoic foci in the parenchyma of the pancreas.

In our experience, pancreatic ductal carcinoma (PDAC) developed in 6 of 112 patients with pancreatolithiasis (5.4%).

4 K Inui et al. Chronic pancreatitis: new developments PV Figure 6 Endoscopic ultrasonography shows hyperechoic foci in the parenchyma of the pancreas. Figure 7 Endoscopic ultrasonography depicts lobularity without honeycombing and a cyst (arrow). PV, portal vein. Early chronic pancreatitis. In our experience, pancreatic ductal carcinoma (PDAC) developed in 6 of 112 patients with pancreatolithiasis (5.4%). Only two of the six patients had resectable stage IB or IIA tumors, illustrating the difficulty of diagnosis at an early stage. Pancreatolithiasis is a high-risk factor for PDAC and has other potential complications, such as pancreatic atrophy and irreversible loss of exocrine and endocrine function. Further, stone recurrence after treatment of pancreatolithiasis is very frequent. Considering the importance of early treatment, diagnostic criteria for chronic pancreatitis were revised in by a study group of the Japanese Ministry of Health, Labour and Welfare for intractable pancreatic diseases, together with the Japan Pancreas Society. The result was a proposed concept of early chronic pancreatitis. According to the new criteria, early chronic pancreatitis is diagnosed when more than two of four items suggesting chronic pancreatitis are present together with characteristic early findings by imaging (mainly endoscopic ultrasonography). The four items are repeated upper abdominal pain, abnormal pancreatic enzyme levels in serum or urine, abnormal pancreatic exocrine function, and continuous heavy drinking of alcohol equivalent to over 80 g/day of pure ethanol. The seven early endoscopic ultrasound (EUS) findings of early chronic pancreatitis (Figs 6,7) include five parenchymal and two ductal abnomalities: (i) lobularity with honeycombing; (ii) lobularity without honeycombing; (iii) hyperechoic foci without shadowing; (iv) stranding; (v) cysts; (vi) dilated side branches; and (vii) hyperechoic MPD margin. More than two features of these seven EUS findings are required, including at least one of (i) to (iv). The aim of adopting the category of early chronic pancreatitis is prevention of development intractable disease by early treatment. Hirota et al. 31 reported distinct clinical features in two patients diagnosed with early chronic pancreatitis, both progressed to definite chronic pancreatitis. Further study is needed to determine whether an instance of early chronic pancreatitis diagnosed using the earlier criteria should be treated as a proven case of chronic pancreatitis, as well as whether abnormal findings can be reversed at this early stage by non-surgical treatments such as abstinence from alcohol, use of oral protease inhibitors, and pancreatic enzyme replacement therapy. Acknowledgment This work was supported in part by the Research Committee of Intractable Pancreatic Diseases (Principal investigator: Tooru Shimosegawa) provided by the Ministry of Health, Labour and Welfares of Japan. References 1 Hirota M, Shimosegawa T, Masamune A et al. The sixth nationwide epidemiological survey of chronic pancreatitis in Japan. Pancreatology 2012; 12: Nardi GL. Technique of sphincteroplasty in recurrent pancreatitis. Surg. Gynecol. Obst. 1960; 110: Puestow CB, Gillesby WJ. Retrograde surgical drainage of pancreas for chronic relapsing pancreatitis. Arch. Surg. 1958; 76: Partington PF, Rochelle REL. Modified Puestow procedure for retrograde drainage of the pancreatic duct. Ann. Surg. 1960; 152: Frey CF, Child CG, Fry W. Pancreatectomy for chronic pancreatitis. Ann. Surg. 1976; 184: Beger HG, Krautzberger W, Bittner R, Büchler M, Limmer J. Duodenum-preserving resection of the head of the pancreas in patients with severe chronic pancreatitis. Surgery 1985; 97: Inui K, Nakae Y, Nakamura J et al. A case of non-calcified pancreatolithiasis which was removed by endoscopic sphincterotomy of the pancreatic duct. Gastroenterol. Endosc. 1983; 25: (in Japanese with English abstract.). Journal of Gastroenterology and Hepatology 2013; 28 (Suppl. 4):

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Endoscopic treatment for chronic pancreatitis: indications, technique, results

J Hepatobiliary Pancreat Sci (2010) 17:770 775 DOI 10.1007/s00534-009-0182-7 TOPICS Chronic pancreatitis: current treatment strategies Endoscopic treatment for chronic pancreatitis: indications, technique,